US8012975B2ExpiredUtilityA1
Antitumoral analogs of ET-743
Est. expiryMay 15, 2020(expired)· nominal 20-yr term from priority
A61P 35/00C07D 491/22C07D 497/22C07D 491/18C07D 471/22C07D 471/18
84
PatentIndex Score
7
Cited by
227
References
74
Claims
Abstract
Antitumor compounds have the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group.
Claims
exact text as granted — not AI-modified1. A compound of the following formula or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is —CH 2 —N(R a ) 2 or —CH 2 —OR a , where R a is H; alkyl-CO—; haloalkyl-CO—; cycloalkylalkyl-CO—; haloalkyl-O—CO—; arylalkyl-CO—; arylalkenyl-CO—; heteroaryl-CO—; alkenyl-CO—; alkenyl; amino acid acyl; or a protecting group;
R 5 is OR″, where R″ is H; alkyl-CO—; cycloalkyl-CO—; haloalkyl-CO—; or a protecting group;
R 18 is —OR, where R is H; alkyl-CO—; cycloalkylalkyl-CO—; or a protecting group; and
R 21 is —OH; provided that
where an amino group is protected, the amino group together with the protecting group forms: (a) a carbamate selected from the group consisting of alkyl, arylalkyl, sulpho- or halo-arylalkyl, alkylsilylalkyl, arylalkyl, cycloalkylalkyl, alkylarylalkyl, heterocyclylalkyl, nitroarylalkyl, acylaminoalkyl, nitroaryldithioarylalkyl, dicycloalkylcarboxamidoalkyl, cycloalkyl, alkenyl, arylalkenyl, nitroarylalkenyl, heterocyclylalkenyl, heterocyclyl, hydroxyheterocyclyl, alkyldithio, alkoxy- or halo- or alkylsulphinyl arylalkyl, and heterocyclylacyl carbamate; (b) an aroyl, arylaroyl, haloaroyl, or nitroaroyl amide; or (c) alkylamino, alkylsilylalkoxyalkylamino, alkoxyalkylamino, cyanoalkylamino, heterocyclylamino, alkoxyarylalkylamino, cycloalkylamino, nitroarylamino, arylalkylamino, or alkoxy- or hydroxy-arylalkylamino;
and where a hydroxy group is protected, the hydroxyl group together with the protecting group forms: (a) an ether selected from the group consisting of alkyl, alkoxyalkyl, aryloxyalkyl, alkoxyalkoxyalkyl, alkylsilylalkoxyalkyl, alkylthioalkyl, arylthioalkyl, azidoalkyl, cyanoalkyl, chloroalkyl, heterocyclic, cycloalkylalkyl, alkenyl, cycloalkyl, alkylarylalkyl, alkoxyarylalkyl, nitroarylalkyl, haloarylalkyl, alkylaminocarbonylarylalkyl, alkylsulfinylarylalkyl and alkylsilyl ether; or (b) arylacyloxy, aryl alkyl carbonate, aliphatic carbonate, alkylsulfinylarylalkyl carbonate, alkyl carbonate, aryl haloalkyl carbonate, aryl alkenyl carbonate, arylcarbamate, alkylphosphinyl, alkylphosphinothioyl, arylphosphinothioyl, or alkyl sulphonate.
2. A compound according to claim 1 , which is of the formula:
3. A compound according to claim 2 wherein:
R 1 is —CH 2 —N(R a ) 2 or —CH 2 —OR a , where R a at each occurrence is, independently, H; alkyl-CO—; haloalkyl-CO—; haloalkyl-O—CO—; arylalkyl-CO—; arylalkenyl-CO—; heteroaryl-CO—; alkenyl-CO—; amino acid acyl; or a protecting group;
R 5 is OH; acetyloxy or other acyloxy group up to 4 carbon atoms; and
R 18 is —OH.
4. A compound according to claim 2 wherein R 1 is —CH 2 —N(R a ) 2 , where R a is H; haloalkyl-CO—; cycloalkylalkyl-CO—; haloalkyl-O—CO—; arylalkyl-CO—; heteroaryl-CO—; alkenyl-CO—; alkenyl; or a protecting group.
5. A compound according to claim 2 wherein R 1 is —CH 2 —OR a .
6. A compound according to claim 3 , wherein R 1 is —CH 2 —NHR a .
7. A compound according to claim 4 , wherein R 1 is —CH 2 —NHR a .
8. A compound according to claim 3 , wherein R a is -aa-R b where aa is amino acid acyl and R b is as defined for R a in claim 3 .
9. A compound according to claim 5 , wherein R a is -aa-R b where aa is amino acid acyl and R b is as defined for R a in claim 5 .
10. A compound according to claim 8 , wherein the amino acid acyl is further substituted with one or more R a groups.
11. A compound according to claim 9 , wherein the amino acid acyl is further substituted with one or more R a groups.
12. A compound according to claim 3 , wherein R 1 is —CH 2 —NH-aa-R b where aa is an amino acid and R b is hydrogen; protecting group; arylalkenyl-CO—; haloalkyl-CO—; alkyl-CO—; arylalkyl-CO—; or amino acid acyl.
13. A compound according to claim 12 , wherein aa is alanine and R b is selected from the group consisting of hydrogen, Boc, PhNHCS—, CF 3 CO—, trans(trifluoromethyl)cinnamoyl, cinnamoyl, C 3 F 7 CO—, butyryl, 3-chloropropionoyl, hydrocinnamoyl, phenylacetyl, and acetyl; aa is valine and R b is selected from the group consisting of Cbz and Boc; aa is phenylalanine and R b is Boc; aa is proline and R b is Boc; aa is arginine and R b is Boc; or aa is tryptophan and R b is Boc.
14. A compound according to claim 3 , wherein R 1 is —CH 2 —NR a -aa-R b where aa is an amino acid, R a is alkyl-CO— and R b is haloalkyl-CO—.
15. A compound according to claim 14 , wherein aa is acetylalanine, R a is acetyl or butyryl, and R b is CF 3 —CO—.
16. A compound according to claim 3 , wherein R 1 is —CH 2 —NHR a where R a is hydrogen; protecting group; alkyl-CO—; alkenyl-CO—; arylalkyl-CO—; arylalkenyl-CO—; or heteroaryl-CO—.
17. A compound according to claim 4 , wherein R 1 is —CH 2 —NHR a where R a is hydrogen; protecting group, alkenyl-CO—; arylalkyl-CO—; heteroaryl-CO—; cycloalkylalkyl-CO—; or alkenyl.
18. A compound according to claim 16 , wherein R a is hydrogen, Troc, acetyl, isovaleroyl, decanoyl, cinnamoyl, hydrocinnamoyl, or phenylacetyl.
19. A compound according to claim 16 , wherein R a is propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, or chloronicotinoyl.
20. A compound according to claim 17 , wherein R a is cyclohexylacetyl, cyclohexylpropionyl, or allyl.
21. A compound according to claim 3 , wherein R 1 is —CH 2 —OR a where R a is hydrogen; a protected cysteine; a protecting group; alkyl-CO—; arylalkyl-CO—; or arylalkenyl-CO—.
22. A compound according to claim 21 , wherein R a is hydrogen; butyryl; trans(trifluoromethyl)cinnamoyl; cinnamoyl; or hydrocinnamoyl.
23. A compound according to claim 5 , wherein R a is selected from the group consisting of hydrogen; a protected cysteine; a cysteine derivative of the formula Prot SH -S—CH 2 —CH(NHProt NH )-CO—, where Prot SH and Prot NH are protecting groups for thiol and for amino; a protecting group; alkyl-CO—; arylalkyl-CO—; arylalkenyl-CO—; a cysteine derivative of the formula Prot SH -S—CH 2 —C(═NOProt OH )-CO— where Prot SH is a protecting group for thiol and Prot OH is a protecting group for hydroxy; and a cysteine derivative of formula Prot SH -S—CH═C(—OProt OH )-CO—, where Prot SH is a protecting group for thiol and Prot OH is a protecting group for hydroxy.
24. A compound according to claim 23 , wherein R a is selected from the group consisting of hydrogen; S—Fm—O-TBDMS-cysteine; a cysteine derivative of the formula Prot SH -S—CH 2 —CH(NHProt NH )-CO— where Prot SH is Fm and Prot NH is Troc; butyryl; (trifluoromethyl)cinnamoyl; cinnamoyl; a cysteine derivative of the formula Prot SH -S—CH 2 —C(═NOProt OH )-CO— where Prot SH is Fm and Prot OH is methoxy; and a cysteine derivative of formula Prot SH -S—CH═C(—OProt OH )-CO—, where Prot SH is Fm and Prot OH is MOM.
25. A compound according to claim 4 , wherein R″ is H; alkyl-CO—, where the alkyl has an odd number of carbon atoms; ω-cyclohexylalkyl-CO—; or a protecting group.
26. A compound according to claim 5 wherein R″ is H; alkyl-CO—, where the alkyl has an odd number of carbon atoms; ω-cyclohexylalkyl-CO—; or a protecting group.
27. A compound according to claim 3 , wherein R 5 is —OCOCH 3 .
28. A compound according to claim 25 , wherein R 5 is —OCOCH 3 .
29. A compound according to claim 26 , wherein R 5 is —OCOCH 3 .
30. A compound according to claim 4 , wherein R is H, alkyl-CO—, or a protecting group.
31. A compound according to claim 5 , wherein R is H, alkyl-CO—, or a protecting group.
32. A compound according to claim 30 , wherein R 18 is —OH.
33. A compound according to claim 31 , wherein R 18 is —OH.
34. A compound according to claim 1 , which is of the formula:
35. A compound according to claim 34 wherein:
R 1 is —CH 2 —N(R a ) 2 or —CH 2 —OR a , where R a at each occurrence is, independently, H; alkyl-CO—; haloalkyl-CO—; haloalkyl-O—CO—; arylalkyl-CO—; arylalkenyl-CO—; heteroaryl-CO—; alkenyl-CO—; amino acid acyl; or a protecting group;
R 5 is OH; acetyloxy or other acyloxy group up to 4 carbon atoms; and
R 18 is —OH;
wherein in the definitions of R a , the alkyl has 1 to 12 carbon atoms, the alkenyl has 2 to 12 carbon atoms, the aryl group is selected from phenyl, biphenyl, and naphthyl, and the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, and S.
36. A compound according to claim 34 wherein R 1 is —CH 2 —N(R a ) 2 , where R a is H; haloalkyl-CO—; cycloalkylalkyl-CO—; haloalkyl-O—CO—; arylalkyl-CO—; heteroaryl-CO—; alkenyl-CO—; alkenyl; or a protecting group;
wherein the alkyl has 1 to 12 carbon atoms, the cycloalkyl has 3 to 12 carbon atoms, the alkenyl has 2 to 12 carbon atoms, the aryl group has 1 to 3 separate or fused rings and from 6 to 18 carbon atoms, and the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, and S.
37. A compound according to claim 34 wherein R 1 is —CH 2 —OR a
wherein the alkyl has 1 to 12 carbon atoms, the cycloalkyl has 3 to 12 carbon atoms, the alkenyl has 2 to 12 carbon atoms, the aryl group has 1 to 3 separate or fused rings and from 6 to 18 carbon atoms, and the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O, and S.
38. A compound according to claim 35 , wherein R 1 is —CH 2 —NHR a .
39. A compound according to claim 36 , wherein R 1 is —CH 2 —NHR a .
40. A compound according to claim 35 , wherein R a is -aa-R b where aa is amino acid acyl and R b is as defined for R a in claim 35 .
41. A compound according to claim 37 , wherein R a is -aa-R b where aa is amino acid acyl and R b is as defined for R a in claim 37 .
42. A compound according to claim 40 , wherein the amino acid acyl is further substituted with one or more R a groups.
43. A compound according to claim 41 , wherein the amino acid acyl is further substituted with one or more R a groups.
44. A compound according to claim 35 , wherein R 1 is —CH 2 —NH-aa-R b where aa is an amino acid and R b is hydrogen; protecting group; arylalkenyl-CO—; haloalkyl-CO—; alkyl-CO—; arylalkyl-CO—; or amino acid acyl, wherein aryl, alkenyl, and alkyl are as defined in claim 35 .
45. A compound according to claim 44 , wherein aa is alanine and R b is selected from the group consisting of hydrogen, Boc, PhNHCS—, CF 3 CO—, trans(trifluoromethyl)cinnamoyl, cinnamoyl, C 3 F 7 CO—, butyryl, 3-chloropropionoyl, hydrocinnamoyl, phenylacetyl, and acetyl; aa is valine and R b is selected from the group consisting of Cbz and Boc; aa is phenylalanine and R b is Boc; aa is proline and R b is Boc; aa is arginine and R b is Boc; or aa is tryptophan and R b is Boc.
46. A compound according to claim 35 , wherein R 1 is —CH 2 —NR a -aa-R b where aa is an amino acid, R a is alkyl-CO— and R b is haloalkyl-CO—, wherein alkyl is as defined in claim 35 .
47. A compound according to claim 46 , wherein aa is acetylalanine, R a is acetyl or butyryl, and R b is CF 3 —CO—.
48. A compound according to claim 35 , wherein R 1 is —CH 2 —NHR a where R a is hydrogen; protecting group; alkyl-CO—; alkenyl-CO—; arylalkyl-CO—; arylalkenyl-CO—; or heteroaryl-CO—.
49. A compound according to claim 36 , wherein R 1 is —CH 2 —NHR a where R a is hydrogen; protecting group, alkenyl-CO—; arylalkyl-CO—; heteroaryl-CO—; cycloalkylalkyl-CO—; or alkenyl.
50. A compound according to claim 48 , wherein R a is hydrogen, Troc, acetyl, isovaleroyl, decanoyl, cinnamoyl, hydrocinnamoyl, or phenylacetyl.
51. A compound according to claim 48 , wherein R a is propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, or chloronicotinoyl.
52. A compound according to claim 49 , wherein R a is cyclohexylacetyl, cyclohexylpropionyl, or allyl.
53. A compound according to claim 35 , wherein R 1 is —CH 2 —OR a where R a is hydrogen; a protected cysteine; a protecting group; alkyl-CO—; arylalkyl-CO—; or arylalkenyl-CO—.
54. A compound according to claim 53 , wherein R a is hydrogen; butyryl; trans(trifluoromethyl)cinnamoyl; cinnamoyl; or hydrocinnamoyl.
55. A compound according to claim 37 , wherein R a is selected from the group consisting of hydrogen; a protected cysteine; a cysteine derivative of the formula Prot SH -S—CH 2 —CH(NHProt NH )-CO—, where Prot SH and Prot NH are protecting groups for thiol and for amino; a protecting group; alkyl-CO—; arylalkyl-CO—; arylalkenyl-CO—; a cysteine derivative of the formula Prot SH -S—CH 2 —C(═NOProt OH )-CO— where Prot SH is a protecting group for thiol and Prot OH is a protecting group for hydroxy; and a cysteine derivative of formula Prot SH -S—CH═C(—OProt OH )-CO—, where Prot SH is a protecting group for thiol and Prot OH is a protecting group for hydroxy.
56. A compound according to claim 55 , wherein R a is selected from the group consisting of hydrogen; S—Fm—O-TBDMS-cysteine; a cysteine derivative of the formula Prot SH -S—CH 2 —CH(NHProt NH )CO— where Prot SH is Fm and Prot NH is Troc; butyryl; (trifluoromethyl)cinnamoyl; cinnamoyl; a cysteine derivative of the formula Prot SH -S—CH 2 —C(═NOProt OH )-CO— where Prot SH is Fm and Prot OH is methoxy; and a cysteine derivative of formula Prot SH -S—CH═C(—OProt OH )-CO—, where Prot SH is Fm and Prot OH is MOM.
57. A compound according to claim 36 , wherein R″ is H; alkyl-CO—, where the alkyl has an odd number of carbon atoms; ω-cyclohexylalkyl-CO—; or a protecting group, wherein alkyl is as defined in claim 36 .
58. A compound according to claim 37 , wherein R″ is H; alkyl-CO—, the alkyl has an odd number of carbon atoms; ω-cyclohexylalkyl-CO—; or a protecting group, wherein alkyl is as defined in claim 37 .
59. A compound according to claim 35 , wherein R 5 is —OCOCH 3 .
60. A compound according to claim 57 , wherein R 5 is —OCOCH 3 .
61. A compound according to claim 58 , wherein R 5 is —OCOCH 3 .
62. A compound according to claim 36 , wherein R is H, alkyl-CO—, or a protecting group.
63. A compound according to claim 37 , wherein R is H, alkyl-CO—, or a protecting group.
64. A compound according to claim 62 , wherein R 18 is —OH.
65. A compound according to claim 63 , wherein R 18 is —OH.
66. A compound with the following general structure (I) or a pharmaceutically acceptable salt thereof:
wherein R′ is selected from CH 2 NHR a , CH 2 OR a , and CH 2 —NH—CO—CHCH 3 —NHR a ; and R a , R 5 , R 18 and R 21 are each independently selected from the groups defined below:
R a
R 5
R 18
R 21
H
OH
OH
OH
COCH 2 CH 2 CH 3
OAc
COCH 2 Ph
COCH 2 CH 2 Ph
COCH═CHPh
COCH(CH 3 )NHCOCH 2 CH 2 Ph
CO—(S)—CH(CH 3 )NHCOCF 3
CO—(R)—CH(CH 3 )NHCOCF 3
CO—(S)—CH(NHCbz)CH(CH 3 ) 2
Boc
CSNHPh
.
67. A compound with the following general structure (II) or a pharmaceutically acceptable salt thereof:
wherein R 1 is selected from CH 2 NHR a , CH 2 OR a , and CH 2 —NH—CO—CHCH 3 —NHR a ; and R a , R 5 , R 18 and R 21 are each independently selected from the groups defined below:
R a
R 5
R 18
R 21
H
OH
OH
OH
COCH 2 CH 2 CH 3
OAc
COCH 2 Ph
COCH 2 CH 2 Ph
COCH═CHPh
COCH(CH 3 )NHCOCH 2 CH 2 Ph
CO—(S)—CH(CH 3 )NHCOCF 3
CO—(R)—CH(CH 3 )NHCOCF 3
CO—(S)—CH(NHCbz)CH(CH 3 ) 2
Boc
CSNHPh
.
68. A compound with the following general structure (III), (IV) or (V) or a pharmaceutically acceptable salt thereof:
wherein R′, X 2 , R 1 and R 6 are each independently selected from the groups defined below:
R
X 2
R 1
R 6
H
OH
OH
OH
CH 2 CH═CH 2
OAc
OAc
COCH 2 CH 3
OCH 2 CH═CH 2
OMOM
OCOOCH 2 CH═CH 2
OCOCH 2 C 6 H 11
CO(CH 2 ) 4 CH 3
OCOCF 3
OCOCH 2 CH 2 C 6 H 11
CO(CH 2 ) 12 CH 3
OCOCH 2 Cl
OCOCH 2 CH 2 CH 3
CO(CH 2 ) 16 CH 3
OCOCH 2 CH 2 Cl
OCO(CH 2 ) 4 CH 3
COCH 2 C 6 H 11
OCOCF 2 CF 2 CF 3
OCO(CH 2 ) 8 CH 3
COCH 2 CH 2 C 6 H 11
OCO(CH 2 ) 16 CH 3
COCH 2 Ph
COCH 2 CH 2 Ph
COCH═CHCH 3
COCH(CH 3 )NHCOCH 2 CH 2 Ph
CO—(S)—CH(NHCbz)CH(CH 3 ) 2
Boc
CSNHPh
.
69. A compound of the following formula or a pharmaceutically acceptable salt thereof:
70. A compound of the following formula or a pharmaceutically acceptable salt thereof:
71. A pharmaceutical composition comprising a compound according to any one of claims 1 , 2 , 3 , 4 , 5 , 34 , 35 , 36 or 37 , together with a pharmaceutically acceptable carrier.
72. A method of treating a mammal affected by bladder cancer, breast cancer, colon cancer, stomach cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, throat cancer, prostate cancer, kidney cancer, retinoblastoma, melanoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leukemia, or lymphoma, which comprises administering a compound according to any one of claims 1 , 2 , 3 , 4 , 5 , 34 , 35 , 36 or 37 .
73. The method according to claim 72 wherein the mammal is a human.
74. A compound of the following formula or a pharmaceutically acceptable salt thereof:Cited by (0)
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